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The capicua-ataxin-1-like complex regulates Notch-driven marginal zone B cell development and sepsis progression

Author

Listed:
  • Jong Seok Park

    (Pohang University of Science and Technology (POSTECH))

  • Minjung Kang

    (Pohang University of Science and Technology (POSTECH))

  • Han Bit Kim

    (Pohang University of Science and Technology (POSTECH))

  • Hyebeen Hong

    (Pohang University of Science and Technology (POSTECH))

  • Jongeun Lee

    (Pohang University of Science and Technology (POSTECH))

  • Youngkwon Song

    (Pohang University of Science and Technology (POSTECH))

  • Yunjung Hur

    (Pohang University of Science and Technology (POSTECH))

  • Soeun Kim

    (Pohang University of Science and Technology (POSTECH))

  • Tae-Kyung Kim

    (Pohang University of Science and Technology (POSTECH))

  • Yoontae Lee

    (Pohang University of Science and Technology (POSTECH)
    Yonsei University)

Abstract

Follicular B (FOB) and marginal zone B (MZB) cells are pivotal in humoral immune responses against pathogenic infections. MZB cells can exacerbate endotoxic shock via interleukin-6 secretion. Here we show that the transcriptional repressor capicua (CIC) and its binding partner, ataxin-1-like (ATXN1L), play important roles in FOB and MZB cell development. CIC deficiency reduces the size of both FOB and MZB cell populations, whereas ATXN1L deficiency specifically affects MZB cells. B cell receptor signaling is impaired only in Cic-deficient FOB cells, whereas Notch signaling is disrupted in both Cic-deficient and Atxn1l-deficient MZB cells. Mechanistically, ETV4 de-repression leads to inhibition of Notch1 and Notch2 transcription, thereby inhibiting MZB cell development in B cell-specific Cic-deficient (Cicf/f;Cd19-Cre) and Atxn1l-deficient (Atxn1lf/f;Cd19-Cre) mice. In Cicf/f;Cd19-Cre and Atxn1lf/f; Cd19-Cre mice, humoral immune responses and lipopolysaccharide-induced sepsis progression are attenuated but are restored upon Etv4-deletion. These findings highlight the importance of the CIC-ATXN1L complex in MZB cell development and may provide proof of principle for therapeutic targeting in sepsis.

Suggested Citation

  • Jong Seok Park & Minjung Kang & Han Bit Kim & Hyebeen Hong & Jongeun Lee & Youngkwon Song & Yunjung Hur & Soeun Kim & Tae-Kyung Kim & Yoontae Lee, 2024. "The capicua-ataxin-1-like complex regulates Notch-driven marginal zone B cell development and sepsis progression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54803-z
    DOI: 10.1038/s41467-024-54803-z
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    References listed on IDEAS

    as
    1. Sungjun Park & Seungwon Lee & Choong-Gu Lee & Guk Yeol Park & Hyebeen Hong & Jeon-Soo Lee & Young Min Kim & Sung Bae Lee & Daehee Hwang & Youn Soo Choi & John D. Fryer & Sin-Hyeog Im & Seung-Woo Lee &, 2017. "Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    2. Shin-ichiro Honda & Kazuki Sato & Naoya Totsuka & Satoshi Fujiyama & Manabu Fujimoto & Kensuke Miyake & Chigusa Nakahashi-Oda & Satoko Tahara-Hanaoka & Kazuko Shibuya & Akira Shibuya, 2016. "Marginal zone B cells exacerbate endotoxic shock via interleukin-6 secretion induced by Fcα/μR-coupled TLR4 signalling," Nature Communications, Nature, vol. 7(1), pages 1-10, September.
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